DiVincenzo Christina, Elzinga Christopher D, Medeiros Adam C, Karbassi Izabela, Jones Jeremiah R, Evans Matthew C, Braastad Corey D, Bishop Crystal M, Jaremko Malgorzata, Wang Zhenyuan, Liaquat Khalida, Hoffman Carol A, York Michelle D, Batish Sat D, Lupski James R, Higgins Joseph J
Quest Diagnostics, Athena Diagnostics Marlborough, Massachusetts.
Departments of Molecular and Human Genetics and Pediatrics, Baylor College of Medicine Houston, Texas.
Mol Genet Genomic Med. 2014 Nov;2(6):522-9. doi: 10.1002/mgg3.106. Epub 2014 Aug 21.
We report the frequency, positive rate, and type of mutations in 14 genes (PMP22, GJB1, MPZ, MFN2, SH3TC2, GDAP1, NEFL, LITAF, GARS, HSPB1, FIG4, EGR2, PRX, and RAB7A) associated with Charcot-Marie-Tooth disease (CMT) in a cohort of 17,880 individuals referred to a commercial genetic testing laboratory. Deidentified results from sequencing assays and multiplex ligation-dependent probe amplification (MLPA) were analyzed including 100,102 Sanger sequencing, 2338 next-generation sequencing (NGS), and 21,990 MLPA assays. Genetic abnormalities were identified in 18.5% (n = 3312) of all individuals. Testing by Sanger and MLPA (n = 3216) showed that duplications (dup) (56.7%) or deletions (del) (21.9%) in the PMP22 gene accounted for the majority of positive findings followed by mutations in the GJB1 (6.7%), MPZ (5.3%), and MFN2 (4.3%) genes. GJB1 del and mutations in the remaining genes explained 5.3% of the abnormalities. Pathogenic mutations were distributed as follows: missense (70.6%), nonsense (14.3%), frameshift (8.7%), splicing (3.3%), in-frame deletions/insertions (1.8%), initiator methionine mutations (0.8%), and nonstop changes (0.5%). Mutation frequencies, positive rates, and the types of mutations were similar between tests performed by either Sanger (n = 17,377) or NGS (n = 503). Among patients with a positive genetic finding in a CMT-related gene, 94.9% were positive in one of four genes (PMP22, GJB1, MPZ, or MFN2).
我们报告了在一家商业基因检测实验室接受检测的17880名个体中，与夏科-马里-图斯病（CMT）相关的14个基因（PMP22、GJB1、MPZ、MFN2、SH3TC2、GDAP1、NEFL、LITAF、GARS、HSPB1、FIG4、EGR2、PRX和RAB7A）的突变频率、阳性率及突变类型。对测序分析和多重连接依赖探针扩增（MLPA）的去识别化结果进行了分析，包括100102次桑格测序、2338次新一代测序（NGS）和21990次MLPA检测。在所有个体中，18.5%（n = 3312）检测到基因异常。桑格测序和MLPA检测（n = 3216）结果显示，PMP22基因的重复（dup）（56.7%）或缺失（del）（21.9%）占阳性结果的大部分，其次是GJB1（6.7%）、MPZ（5.3%）和MFN2（4.3%）基因的突变。GJB1缺失及其余基因的突变占异常结果的5.3%。致病突变分布如下：错义突变（70.6%）、无义突变（14.3%）、移码突变（8.7%）、剪接突变（3.3%）、框内缺失/插入（1.8%）、起始甲硫氨酸突变（0.8%）和非终止突变（0.5%）。桑格测序（n = 17377）或NGS（n = 503）检测的突变频率、阳性率及突变类型相似。在CMT相关基因检测呈阳性的患者中，94.9%在四个基因（PMP22、GJB1、MPZ或MFN2）之一中呈阳性。
